Abstract 129: RAD17 loss of function is synthetically lethal with the checkpoint kinase inhibitors AZD7762 or MK-1775

2015 ◽  
Author(s):  
John Paul Shen ◽  
Rohith Srivas ◽  
Ana Bojorquez-Gomez ◽  
Katherine Licon ◽  
Vignesh Sivaganesh ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Loss Of Function ◽  
Checkpoint Kinase ◽  
Synthetically Lethal

scholarly journals Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy

2015 ◽  
Vol 113 (1) ◽  
pp. 182-187 ◽  
Author(s):  
Christina H. Eng ◽  
Zuncai Wang ◽  
Diane Tkach ◽  
Lourdes Toral-Barza ◽  
Savuth Ugwonali ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Cell Types ◽  
Loss Of Function ◽  
Growth And Survival ◽  
Oncogenic Mutations ◽  
Cellular Context ◽  
Genetic Stratification

Macroautophagy is a key stress-response pathway that can suppress or promote tumorigenesis depending on the cellular context. Notably, Kirsten rat sarcoma (KRAS)-driven tumors have been reported to rely on macroautophagy for growth and survival, suggesting a potential therapeutic approach of using autophagy inhibitors based on genetic stratification. In this study, we evaluated whether KRAS mutation status can predict the efficacy to macroautophagy inhibition. By profiling 47 cell lines with pharmacological and genetic loss-of-function tools, we were unable to confirm that KRAS-driven tumor lines require macroautophagy for growth. Deletion of autophagy-related 7 (ATG7) by genome editing completely blocked macroautophagy in several tumor lines with oncogenic mutations in KRAS but did not inhibit cell proliferation in vitro or tumorigenesis in vivo. Furthermore, ATG7 knockout did not sensitize cells to irradiation or to several anticancer agents tested. Interestingly, ATG7-deficient and -proficient cells were equally sensitive to the antiproliferative effect of chloroquine, a lysosomotropic agent often used as a pharmacological tool to evaluate the response to macroautophagy inhibition. Moreover, both cell types manifested synergistic growth inhibition when treated with chloroquine plus the tyrosine kinase inhibitors erlotinib or sunitinib, suggesting that the antiproliferative effects of chloroquine are independent of its suppressive actions on autophagy.

The Challenge of Combining Chemo- and Radiotherapy with Checkpoint Kinase Inhibitors

2020 ◽  
Author(s):  
Linda van Bijsterveldt ◽  
Samuel C. Durley ◽  
Tim S. Maughan ◽  
Timothy C. Humphrey
Keyword(s):  
Kinase Inhibitors ◽  
Checkpoint Kinase

scholarly journals Loss of Function SETD2 Mutations in Poorly Differentiated Metastases from Two Hürthle Cell Carcinomas of the Thyroid

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1892
Author(s):  
Valeria Pecce ◽  
Antonella Verrienti ◽  
Luana Abballe ◽  
Raffaella Carletti ◽  
Giorgio Grani ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Active Form ◽  
The Novel ◽  
Loss Of Function ◽  
Ww Domains ◽  
Functional Studies ◽  
Hürthle Cell ◽  
Mutational Status ◽  
Poorly Differentiated ◽  
Differentiated Thyroid Cancers

Hürthle cell carcinomas (HCC) are rare differentiated thyroid cancers that display low avidity for radioactive iodine and respond poorly to kinase inhibitors. Here, using next-generation sequencing, we analyzed the mutational status of primary tissue and poorly differentiated metastatic tissue from two HCC patients. In both cases, metastatic tissues harbored a mutation of SETD2, each resulting in loss of the SRI and WW domains of SETD2, a methyltransferase that trimethylates H3K36 (H3K36me3) and also interacts with p53 to promote its stability. Functional studies of the novel p.D1890fs6* mutation (case 1) revealed significantly reduced H3K36me3 levels in SETD2-mutated tissue and primary cell cultures and decreased levels of the active form of p53. Restoration of SETD2-wildtype expression in the SETD2-mutant cells significantly reduced the expression of four well-known stemness markers (OCT-4, SOX2, IPF1, Goosecoid). These findings suggest potential roles for SETD2 loss-of-function mutations in HCC progression, possibly involving p53 destabilization and promotion of stemness. Their prevalence and potential treatment implications in thyroid cancer, especially HCC, require further study.

scholarly journals G2 Checkpoint Kinase Inhibitors Exert Their Radiosensitizing Effects Prior to the G2/M Transition

Cell Cycle ◽  
2007 ◽  
Vol 6 (5) ◽  
pp. 572-575 ◽  
Author(s):  
Christopher M. Sturgeon ◽  
Michel Roberge
Keyword(s):  
Kinase Inhibitors ◽  
Checkpoint Kinase ◽  
G2 Checkpoint

scholarly journals Prohibitin Family Members Interact Genetically with Mitochondrial Inheritance Components in Saccharomyces cerevisiae

1998 ◽  
Vol 18 (7) ◽  
pp. 4043-4052 ◽  
Author(s):  
Karen H. Berger ◽  
Michael P. Yaffe
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Outer Membrane ◽  
Integral Membrane Proteins ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Morphology ◽  
Mitochondrial Inheritance ◽  
Loss Of Function ◽  
Wild Type ◽  
Mitochondrial Inner Membrane ◽  
Synthetically Lethal

ABSTRACT Phb2p, a homolog of the tumor suppressor protein prohibitin, was identified in a genetic screen for suppressors of the loss of Mdm12p, a mitochondrial outer membrane protein required for normal mitochondrial morphology and inheritance in Saccharomyces cerevisiae. Phb2p and its homolog, prohibitin (Phb1p), were localized to the mitochondrial inner membrane and characterized as integral membrane proteins which depend on each other for their stability. In otherwise wild-type genetic backgrounds, null mutations in PHB1 andPHB2 did not confer any obvious phenotypes. However, loss of function of either PHB1 or PHB2 in cells with mitochondrial DNA deleted led to altered mitochondrial morphology, and phb1 or phb2 mutations were synthetically lethal when combined with a mutation in any of three mitochondrial inheritance components of the mitochondrial outer membrane, Mdm12p, Mdm10p, and Mmm1p. These results provide the first evidence of a role for prohibitin in mitochondrial inheritance and in the regulation of mitochondrial morphology.

scholarly journals PHLPPing the balance: restoration of protein kinase C in cancer

2021 ◽  
Vol 478 (2) ◽  
pp. 341-355 ◽  
Author(s):  
Hannah Tovell ◽  
Alexandra C. Newton
Keyword(s):  
Protein Kinase ◽  
Human Disease ◽  
Kinase Inhibitors ◽  
Phorbol Esters ◽  
Meta Analysis ◽  
Cellular Growth ◽  
Negative Regulator ◽  
Loss Of Function ◽  
Tumour Suppressive Function ◽  
The Stability

Protein kinase signalling, which transduces external messages to mediate cellular growth and metabolism, is frequently deregulated in human disease, and specifically in cancer. As such, there are 77 kinase inhibitors currently approved for the treatment of human disease by the FDA. Due to their historical association as the receptors for the tumour-promoting phorbol esters, PKC isozymes were initially targeted as oncogenes in cancer. However, a meta-analysis of clinical trials with PKC inhibitors in combination with chemotherapy revealed that these treatments were not advantageous, and instead resulted in poorer outcomes and greater adverse effects. More recent studies suggest that instead of inhibiting PKC, therapies should aim to restore PKC function in cancer: cancer-associated PKC mutations are generally loss-of-function and high PKC protein is protective in many cancers, including most notably KRAS-driven cancers. These recent findings have reframed PKC as having a tumour suppressive function. This review focusses on a potential new mechanism of restoring PKC function in cancer — through targeting of its negative regulator, the Ser/Thr protein phosphatase PHLPP. This phosphatase regulates PKC steady-state levels by regulating the phosphorylation of a key site, the hydrophobic motif, whose phosphorylation is necessary for the stability of the enzyme. We also consider whether the phosphorylation of the potent oncogene KRAS provides a mechanism by which high PKC expression may be protective in KRAS-driven human cancers.

scholarly journals Variants in the ASXL1 and DMNT3A genes are potential markers of the effectiveness of tyrosine kinase inhibitors therapy in chronic myeloid leukemia

2020 ◽  
pp. 88-89
Author(s):  
Э.П. Адильгереева ◽  
А.Г. Никитин ◽  
Д.Г. Жегло ◽  
О.А. Шухов ◽  
С.А. Смирнихина ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Great Success ◽  
Targeted Drugs ◽  
Loss Of Function

Хронический миелоидный лейкоз (ХМЛ) - онкогематологическое заболевание. Благодаря разработке таргетных препаратов ингибиторов тирозинкиназ (ИТК) достигнуты большие успехи в лечении ХМЛ, однако около 20-40% пациентов резистентны к терапии. Цель исследования - обнаружение экзомных вариантов, обуславливающих различную эффективность терапии ХМЛ. Нами было проведено севенирование экзома 60 пациентов, страдающих ХМЛ, на платформе Illumina NextSeq® 550 Sequencing System. Были обнаружены варианты в генах ASXL1, DNMT3A в группе пациентов, резистентных к терапии ИТК. Выявленные варианты могут быть ассоциированы с резистентностью к терапии ИТК. Chronic myeloid leukemia (CML) is an oncohematological disease. Great success has been achieved in the treatment of CML due to the development of targeted drugs for tyrosine kinase inhibitors (TKI), but about 20-40% of patients are resistant to therapy. The aim of the study was the detection of exome variants causing resistance to CML therapy. We examined the exomes of 60 CML patients using the Illumina NextSeq® 550 Sequencing System platform. In the group of patients resistant to TKI therapy, loss-of-function variants were revealed in the ASXL1 and DNMT3A genes. Identified variants may be associated with resistance to TKI therapy.

scholarly journals Transcriptomic analysis and novel insights into lens fibre cell differentiation regulated by Gata3

Open Biology ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 190220
Author(s):  
Elena Martynova ◽  
Yilin Zhao ◽  
Qing Xie ◽  
Deyou Zheng ◽  
Ales Cvekl
Keyword(s):  
Cell Differentiation ◽  
Transcriptional Control ◽  
Kinase Inhibitors ◽  
Neuroendocrine Cells ◽  
Intermediate Filament Protein ◽  
Loss Of Function ◽  
Fibre Cell ◽  
Lens Fibre ◽  
Lens Fibre Cell

Gata3 is a DNA-binding transcription factor involved in cellular differentiation in a variety of tissues including inner ear, hair follicle, kidney, mammary gland and T-cells. In a previous study in 2009, Maeda et al . ( Dev. Dyn. 238 , 2280–2291; doi:10.1002/dvdy.22035 ) found that Gata3 mutants could be rescued from midgestational lethality by the expression of a Gata3 transgene in sympathoadrenal neuroendocrine cells. The rescued embryos clearly showed multiple defects in lens fibre cell differentiation. To determine whether these defects were truly due to the loss of Gata3 expression in the lens, we generated a lens-specific Gata3 loss-of-function model. Analogous to the previous findings, our Gata3 null embryos showed abnormal regulation of cell cycle exit during lens fibre cell differentiation, marked by reduction in the expression of the cyclin-dependent kinase inhibitors Cdkn1b/p27 and Cdkn1c/p57, and the retention of nuclei accompanied by downregulation of Dnase IIβ. Comparisons of transcriptomes between control and mutated lenses by RNA-Seq revealed dysregulation of lens-specific crystallin genes and intermediate filament protein Bfsp2. Both Cdkn1b/p27 and Cdkn1c/p57 loci are occupied in vivo by Gata3, as well as Prox1 and c-Jun, in lens chromatin. Collectively, our studies suggest that Gata3 regulates lens differentiation through the direct regulation of the Cdkn1b/p27and Cdkn1c/p57 expression, and the direct/or indirect transcriptional control of Bfsp2 and Dnase IIβ.

scholarly journals LZTR1 is a regulator of RAS ubiquitination and signaling

Science ◽  
2018 ◽  
Vol 362 (6419) ◽  
pp. 1171-1177 ◽  
Author(s):  
Johannes W. Bigenzahn ◽  
Giovanna M. Collu ◽  
Felix Kartnig ◽  
Melanie Pieraks ◽  
Gregory I. Vladimer ◽  
...  
Keyword(s):  
Leucine Zipper ◽  
Kinase Inhibitors ◽  
Mapk Pathway ◽  
Resistance Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Loss Of Function ◽  
Pathway Activation ◽  
Mitogen Activated Protein ◽  
Human Disorders ◽  
Ras Isoforms

In genetic screens aimed at understanding drug resistance mechanisms in chronic myeloid leukemia cells, inactivation of the cullin 3 adapter protein-encoding leucine zipper-like transcription regulator 1 (LZTR1) gene led to enhanced mitogen-activated protein kinase (MAPK) pathway activity and reduced sensitivity to tyrosine kinase inhibitors. Knockdown of theDrosophila LZTR1orthologCG3711resulted in a Ras-dependent gain-of-function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation ofLZTR1led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). We propose that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. BecauseLZTR1disease mutations failed to revert loss-of-function phenotypes, our findings provide a molecular rationale forLZTR1involvement in a variety of inherited and acquired human disorders.

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